SUMMARY The apelin receptor (APLNR) agonist program project is seeking to discover an orally active small molecule drug to preserve and improve the heart?s right ventricular (RV) function in patients suffering from pulmonary arterial hypertension (PAH), a devastating disease with high morbidity and mortality. There is compelling evidence that RV function is a major determinant of clinical outcomes in PAH patients. Despite this, none of the current therapies directly improve RV function, perhaps explaining the lack of convincing evidence of a reduction in mortality with any of the current therapeutic mechanisms. Impaired apelin-APLNR signaling has been found in multiple preclinical and clinical studies to be associated with pathogenesis of PAH and RV failure, and infusion of apelin peptide has been found to significantly improve cardiac output without any demonstrated adverse effects. Any potential therapeutic use of the peptide itself, however, is limited by its extremely short half -life (estimated to be less than 5 min in serum). A therapeutic, small molecule-based alternative that can robustly activate APLNR signaling and afford comparable clinical benefits as the peptide long-term would represent a potential paradigm shift in our management of patients with PAH and RV failure. Our chemistry program will use structure-based drug design to improve the pharmacokinetics and drug properties of a published small molecule APLNR agonist with a longer half-life in animals, that also demonstrated robust in vivo activity in single dose acute studies. Using a recently developed robust model of pulmonary hypertension in which the RV undergoes severe, pathologic remodeling in rats, we will investigate the therapeutic efficacy of our improved APLNR agonists, with planned advancement into a robust pig-based RV failure study in the Phase II of this Program upon the successful completion of Phase I.